Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM)

• ClinicalTrials.gov Identifier: NCT00704730
• Recruitment Status: Completed
• First Posted: June 25, 2008
• Results First Posted: September 9, 2014
• Last Update Posted: April 20, 2021
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: June 23, 2008
• First Posted Date: June 25, 2008
• Results First Submitted Date: April 8, 2014
• Results First Posted Date: September 9, 2014
• Last Update Posted Date: April 20, 2021
• Study Start Date: June 2008
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 29, 2014)

Progression-Free Survival (PFS) [ Time Frame: Treatment period consisted of 4-week cycles with radiologic tumor assessment every 12 weeks from date of randomization until date of first documented PD or date of death from any cause, whichever came first, assessed up to 34 months. ]

The duration of Progression-Free Survival (PFS) using progression events as determined by Independent Review Committee (IRC) per mRECIST, or death due to any cause. The analysis was conducted after at least 315 subjects were randomized and at least 138 events were observed.

• Original Primary Outcome Measures (submitted: June 23, 2008): To evaluate progression-free survival (PFS) with XL184 treatment as compared with placebo in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC) [ Time Frame: Assessed at periodic visits ]

Current Secondary Outcome Measures (submitted: August 29, 2014)

• Overall Survival (OS) With XL184 Compared With Placebo [ Time Frame: The pre-specified interim analysis of Overall Survival (OS) was assessed at 44% of required events. Includes data up to 15June2011. As of this date, the number of deaths required to conduct the primary analysis had not been reached. ]
  Duration of Overall Survival (OS) from the time of randomization to death due to any cause. A Kaplan-Meier analysis was performed to estimate the median.
• Objective Response Rate (ORR) [ Time Frame: Assessed at the same time as primary analysis of Progression Free Survival (PFS) data. Assessed at baseline and every 12 weeks until Progressive Disease (PD) up to 34 months. ]
  The proportion of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Independent Review Committee (IRC.) Per Response Evaluation Criteria in Solid Tumor Criteria (mRECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR) disappearance of all target lesions; Partial Response (PR) ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) ≥ 20% increase in the sum of the longest diameter of target lesions. Overall Response Rate: ORR=CR +PR
• Duration of Objective Response (OR): Independent Radiology Committee (IRC) Determined [ Time Frame: From time of first documentation of Objective Response (OR), confirmed at a later visit ≥28 days later as Progressive Disease (PD) as defined by mRECIST or death due to any cause, assessed up to 34 months. ]
  For those subjects with Independent Radiology Committee (IRC) determined Objective Response Rate (ORR), the amount of time from documentation of Objective Response (OR) until Progressive Disease (PD) by mRECIST or death due to any cause.
• Biochemical Response Calcitonin (CTN) % [ Time Frame: Serum tumor markers CTN evaluated from blood samples collected at screening and every 12 weeks (±5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months. ]
  For each on-treatment tumor marker assessment from each subject, the biochemical response of CTN was determined based on percent increase or decrease from baseline. Best biochemical response over course of treatment was determined from evaluation of subject's time point response data. Biochemical response criteria: Complete Response (CR) - decrease in tumor marker into normal range from baseline value; Partial Response (PR) - decrease of >50% from baseline value when baseline value is above normal range; Stable Disease (SD) - no more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD) - increase of >50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE) - missing baseline value / or baseline value is not elevated and response is not PD / or response can not be determined due to change in assay format.
• Biochemical Response Carcinoembryonic Antigen (CEA) % [ Time Frame: Serum tumor markers CEA evaluated from blood samples collected at screening and every 12 weeks (± 5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months. ]
  For each on-treatment tumor marker assessment from each subject, the biochemical response of CEA was determined based on percent increase or decrease from baseline. Best biochemical response over the course of treatment was determined from evaluation of each subject's time point response data. Biochemical response: Complete Response (CR)- Decrease in tumor marker into normal range from baseline value; Partial Response (PR)- Decrease of >50% from baseline value when baseline value is above normal range; Stable Disease (SD)- No more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD)- Increase of >50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE)- Missing baseline value / or baseline value is not elevated and response is not Progressive Disease (PD) / or response can not be determined due to change in assay format.

Original Secondary Outcome Measures (submitted: June 23, 2008)

• To evaluate overall survival (OS) with XL184 treatment as compared with placebo [ Time Frame: Assessed as applicable ]
• To evaluate the objective response rate (ORR) and duration of response in subjects with measurable disease with XL184 treatment as compared with placebo [ Time Frame: Assessed at periodic visits ]
• To evaluate the safety and tolerability of XL184 treatment [ Time Frame: Assessed at periodic visits ]
• To assess the pharmacokinetics and pharmacodynamic effects of XL184 treatment [ Time Frame: Assessed at periodic visits ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer
• Official Title: An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer

Brief Summary

The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.

The Clinical Steering Committee for this study, comprised of study doctors who specialize in medullary thyroid cancer, has provided guidance regarding the design of the study. The committee includes: Douglas Ball, MD, Barry Nelkin, PhD, Martin Schlumberger, MD and Steven Sherman, MD.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Thyroid Cancer

Intervention

• Drug: XL184
  Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily
• Drug: Placebo
  Gelatin capsules color and size-matched to XL184 capsules administered orally daily

Study Arms

• Experimental: 1
  Intervention: Drug: XL184
• Placebo Comparator: 2
  Intervention: Drug: Placebo

Publications *

• Schlumberger M, Elisei R, Muller S, Schoffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, Cohen EEW, Wirth L, Ali H, Clary DO, Yaron Y, Mangeshkar M, Ball D, Nelkin B, Sherman S. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017 Nov 1;28(11):2813-2819. doi: 10.1093/annonc/mdx479.
• Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46. doi: 10.1200/JCO.2012.48.4659. Epub 2013 Sep 3. Erratum In: J Clin Oncol. 2014 Jun 10;32(17):1864.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 29, 2014): 330
• Original Estimated Enrollment (submitted: June 23, 2008): 315
• Actual Study Completion Date: September 2020
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The subject has a histologically confirmed diagnosis of MTC that cannot be removed by surgery, is locally advanced, or has spread in the body.
• The subject is at least 18 years old.
• The subject has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2.
• The subject has documented worsening of disease (progressive disease) at screening compared with a previous CT scan or MRI image done within 14 months of screening.
• The subject has recovered from clinically significant adverse events (side effects) due to any other medications that were administered prior to randomization.
• The subject has adequate organ and bone marrow function.
• Subjects who are sexually active (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments.
• The subject has no other diagnosis of cancer (unless non-melanoma skin cancer, an early form of cervical cancer, or another cancer diagnosed ≥ 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or an early form of cervical cancer).
• Female subjects of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

• The subject has received prior treatment for their cancer within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C).
• The subject has received radiation to ≥ 25 % of bone marrow.
• The subject has received treatment with other investigational agents (unapproved therapies) within 4 weeks of randomization.
• The subject has received treatment with XL184.
• The subject has brain metastases or spinal cord compression, unless completed radiation therapy ≥ 4 weeks prior to randomization and stable without steroid and without anti-convulsant treatment for ≥ 10 days.
• The subject has a history of clinically significant episodes of vomiting blood or a recent history of vomiting > 2.5 mL (about 1/2 teaspoon) of red blood.
• The subject has serious illness other than cancer.
• The subject is pregnant or breastfeeding.
• The subject has an active infection requiring ongoing treatment.
• The subject is incapable of understanding and complying with the protocol or unable to provide informed consent.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Brazil, Canada, Chile, Denmark, France, Germany, Greece, India, Israel, Italy, Korea, Republic of, Netherlands, Peru, Poland, Portugal, Russian Federation, Saudi Arabia, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT00704730
• Other Study ID Numbers: XL184-301
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Exelixis
• Original Responsible Party: Ron Weitzman, MD/Vice President, Clinical Research, Exelixis
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: March 2021